International prospective observational study investigating the disease course and heterogeneity of paediatric-onset inflammatory bowel disease: the protocol of the PIBD-SETQuality inception cohort study

Introduction Patients with paediatric-onset inflammatory bowel disease (PIBD) may develop a complicated disease course, including growth failure, bowel resection at young age and treatment-related adverse events, all of which can have significant and lasting effects on the patient’s development and quality of life. Unfortunately, we are still not able to fully explain the heterogeneity between patients and their disease course and predict which patients will respond to certain therapies or are most at risk of developing a more complicated disease course. To investigate this, large prospective studies with long-term follow-up are needed. Currently, no such European or Asian international cohorts exist. In this international cohort, we aim to evaluate disease course and which patients are most at risk of therapy non-response or development of complicated disease based on patient and disease characteristics, immune pathology and environmental and socioeconomic factors. Methods and analysis In this international prospective observational study, which is part of the PIBD Network for Safety, Efficacy, Treatment and Quality improvement of care (PIBD-SETQuality), children diagnosed with inflammatory bowel disease <18 years are included at diagnosis. The follow-up schedule is in line with standard PIBD care and is intended to continue up to 20 years. Patient and disease characteristics, as well as results of investigations, are collected at baseline and during follow-up. In addition, environmental factors are being assessed (eg, parent’s smoking behaviour, dietary factors and antibiotic use). In specific centres with the ability to perform extensive immunological analyses, blood samples and intestinal biopsies are being collected and analysed (flow cytometry, plasma proteomics, mRNA expression and immunohistochemistry) in therapy-naïve patients and during follow-up. Ethics and dissemination Medical ethical approval has been obtained prior to patient recruitment for all sites. The results will be disseminated through peer-reviewed scientific publications. Trial registration number NCT03571373.

-Title. The title doesn't include information on the specific aim of the study. Given the importance of this work, I would suggest a slight change as follows to grab the reader's eye even more. "A global prospective observational study investigating IBD disease course and its heterogeneity in children and adolescents: the PIBD-SETQuality inception cohort". -Abstract: page 3, line 46 -I would suggest 2-3 examples of the immunological analyses that will be performed and of the biomaterial that will be collected in order to provide the reader with a clearer and more specific understanding of the work planned. Following is a suggestion of examples that could be added to the abstract: "In addition, environmental factors are being assessed (e.g. parent's smoking behaviour, dietary factors, antibiotic use, appendicectomy). In specific centres with the ability to perform extensive immunological analyses (e.g. plasma proteome analysis, peripheral blood T cell analysis, mRNA analysis of biopsies), biomaterial (i.e. blood samples and intestinal biopsies) is being collected and analysed in therapy naïve patients at baseline and during follow-up". -Introduction is comprehensive, focused and thorough.
-Article summary (page 5, lines 14 and 27): Clear and focused. Similarly to my comments above, I would provide a few examples of immunological analysis and quality of life measures to inform and guide the reader on the specific analyses planned. Example as follows: "Performance of extensive immunological analysis (e.g. peripheral blood cell functional analysis, target quantitative mRNA analysis) of blood and biopsies in therapy-naïve patients …" "Large scale-collection of quality of life measures (e.g. IMPACT III and EQ-5D questionnaires) to correlate … " - Table 1 on page 9: I would briefly specify how you describe/define disease course, to give the reader a clearer idea of the specific entities analysed. Example as follows: Course of disease (i.e. achievement of remission and/or response to therapy at 3 months, 6 months, 1 year based on wPCDAI, PUCAI; need for treatment escalation within one year; moderatesevere disease during 6-12 months; development of complications such as fibro-stricturing disease, penetrating disease, perianal disease; need for surgery; need for biologic use after 1-3-5-10-15 and 20 years) -Further comments related to Table 1: Ethnicity: this factor may be a confounder in the molecular analyses (e.g. mRNA) because of genetic variations across different ethnic groups and consequent variation in gene expression. Therefore, breaking down the patients' data by ethnicity is likely to be required. How do you plan to maintain an adequate subpopulation size and statistical power in this respect? Has this been considered in the Power calculation? (i.e. any minimum number of patient per ethnic group required?) Faecal calprotectin is listed in Table 1 but not mentioned in the text, nor in Table 2. Will it be tested and matched to clinical and endoscopic activity scores at different time points to define disease remission or relapse?
Diet is in the list of environmental factors that will be analysed: how will you be able to correct for variation across different European and Asian populations? Will the assessment be based on questionnaire(s)? If so, which one(s)?
-Eligibility criteria, page 12 line 25 "Children and adolescents < 18 years with a likely or confirmed diagnosis of IBD are eligible." Biomaterial -page 14, lines 20-24 "Patients enrolled in the subcohort in whom the diagnosis of IBD is not confirmed after additional investigations will be analysed as non-IBD controls". Please provide more information about the number of control patients you are aiming to. Any power calculations for this? -Eligibility criteria page 12 line 43 -44: Patients are excluded from this study 1) when they are on similar treatments as for IBD but for other conditions. Please provide some details to this statement. Does this refer to any immune-suppressants and/or corticosteroids and/or biological treatments?
-Recruitment and data collection -Biomaterial -page 14, line 3 "In several centres biological specimens are collected in addition to the clinical data … intestinal biopsies from affected and nonaffected tissue are collected prior to treatment initiation …" -Are biopsies going to be collected from specific gut segments? E.g. terminal ileum, right colon, left colon … Will it be the same for Crohn's and UC? Please specify how many biopsies will be collected from which gut location.
-Outcome measures page 14 In the absence of a unifying score to categorise disease course in IBD, I fully agree with the choice of primary and secondary outcome measures for this study. Irrespective of whether a patient will be managed with a step-up or top-down approach based on the severity of their disease presentation or course, these outcome parameters are likely to capture the main events reflecting disease severity, that will be subsequently correlated to clinical and environmental variables.
-Outcome measures -page 15, line 26 -3) the need for surgery Does this refer to IBD related GI surgery or also to surgery for perianal disease? Please specify.
-How many patients have been recruited so far and across how many participating centres? How will you manage missing data/ loss of follow-up?
Minor comments: -Page 12, line 31: Please check: "If A diagnosis OF IBD is not confirmed after …" -Page 14, line 3: Please check: "In several centres biological specimens ARE collected … "

GENERAL COMMENTS
General: Several papers have been published over the last decade noticing a more severe disease course in paediatric IBD than in adult onset IBD. As the prospective long-term paediatric observational studies are scares, this study is highly relevant and the efforts from the authors in constructing this IBD inception cohort are warmly welcomed. To improve the readability of this paper, however, the authors should revise the language as several sentences are unnecessarily difficult to read due to long sentence structures. Moreover, the main outcome (prediction of complicated disease course and therapy response) should be stated precisely and presented earlier in the protocol.
Abstract: PIBD is defined as paediatric IBD. As the study period is 20 years, I think this should be changed to paediatric onset IBD. Do the authors in truth believe that the inclusion of six countries in Asia and Europe is a Global cohort?
Summary: 2nd bullet: I am unsure of how to read this point. Is it a strength/limitation that immunological analyses are performed or is it a strength/limitation that you are testing the performance of the immunological analyses.

Introduction:
Same objection to the definition of PIBD as in the abstract. The use of the Jess et al reference (number 11) regarding treatment-related adverse effects seems off, as Jess does not report on this subject in the given paper and the main focus is not paediatric onset. Moreover (and importantly), there are several paediatric papers reporting on this specific issue.
Objectives: This section is quite vaguely written, and it seems that the authors here state the aims of the study without any objectives. This is a shame as it would improve the oversight of the study for the reader.
The authors state that they will assess the impact of diet on disease course, however, I am confused on how the authors will quantify diets.
It is stated that they will perform a genetic status. To me that means full GWAS, however, this is not planed, as far as I can understand.
Methods and analysis: Table 2: As I understand this is a time-line for the entire study. However, the time-line starts at "time after start of therapy". Should it not be "time from diagnosis"? Eligibility: The authors state that a non-validated questionnaire is utilised to assess school attendance. Would it not be worth the while to validate such a questionnaire before deciding to use it in this very ambitious project?
Biomaterial: Are the sites of biopsy harvesting standardized or can the biopsies originate from any part of the GI-tract? This will create a very heterogeneous study material difficult to analyse.
mRNA is not defined.
Outcome measures: At baseline, clinical characteristics will be compared in patients with active disease. I am confused. Will all patients not be included at diagnosis and will all patients not have active disease at diagnosis?
Immunological biomarkers will be evaluated in treatment naïve patients. Are all patients in the study not treatment naïve (with regards to the exclusion criteria)?
In line 51: location should be localization.
In line 57: earlier should be early.
Sample size: The authors state that 535 patients are needed. Previously, however, they stated that at least 500 patients would be included. Moreover, on clinicaltrials.gov (clinicaltrials.gov/ct2/show/NCT03571373) they state that 1000 patients will be included. These numbers should be in agreement.

GENERAL COMMENTS
With this manuscript the authors publish the protocol of an ongoing global prospective observational study in paediatric IBD (PIBD-SETQuality inception cohort), in order inform interested community members about this study. The most significant new aspect of this protocol is the inclusion of patients before the establishment of the definitive diagnosis. This enables the researchers to examine treatment naive biopsy specimens and blood samples. The second most important aspect is the intended follow-up of twenty years. The collected data will enable the researches to find predictive factors for the different types of disease evolution. The submitted paper is however a summary report of the detailed protocol and therefore some questions remain.
Which is the minimum age for inclusion? The questionnaires used are those for school-age children. Are children with very early or early-onset IBD excluded? Are the questionnaires used validated for all European, Arab and Asian languages? As patients are included before endoscopic confirmation of the disease: how many patients will have to be, or have already been excluded after endoscopies because of change of diagnosis? Will these patients serve as controls? How many drop-outs during the 20 years of follow-up do you estimate will occur? In 2019, the rate of patients continuing their participation in the Swiss-IBD cohort study registry initiated in 2006 for adults (in 2008 for children) is 71%. Kugathasan S, et al., Lancet 2017;389:1710-18 planned to enroll 1100 pediatric patients to gain sufficient power for the identification of ten risk factors for B2 and B3 outcomes. Furthermore, they anticipated a 9% drop out over 3 years. In this protocol the power calculation is based on the primary outcome, i.e. clinical remission at one year. Are 535 patients really enough, considering that, after 20 years you also want to find predictive factors for complicated disease evolution? Why do you not take the occasion to collect stool and/or saliva specimens at different time points for microbiological analyses? Why do you plan to stop the follow-up after 20 years? A lifelong registry of IBD patients would be of great value.

Reviewers' Comments to Author:
Reviewer: 1 Reviewer Name: Marco Gasparetto Institution and Country: The Royal London Children's Hospital, Barts Health Trust, Department of Paediatric Gastroenterology, London, United Kingdom Please state any competing interests or state 'None declared': None declared.
I notice that two co-authors are affiliated to the University linked to the Trust I am currently based at. One of these two Authors also practises as a clinician in the same Unit where I am based. Nevertheless, this has not influenced my assessment of the work to any extent as I have never been directly or indirectly involved in this project so far. Therefore, there are no competing interests.
Please leave your comments for the authors below Comments for the Authors: 1) This work is extremely relevant to the current needs of children and adolescents with IBD. Identification and/or development of prognostic biomarkers is urgently required to improve quality of care by stratifying patients based on their risk for severe disease and by personalising their treatments accordingly.
We thank the reviewer for his appreciation of this study and the thorough review of this manuscript.
2) Title. The title doesn't include information on the specific aim of the study. Given the importance of this work, I would suggest a slight change as follows to grab the reader's eye even more. "A global prospective observational study investigating IBD disease course and its heterogeneity in children and adolescents: the PIBD-SETQuality inception cohort".
We thank the reviewer for his suggestion. We revised the title of the manuscript accordingly, while also taking into account the suggestions from other reviewers and the editor.
3) Abstract: page 3, line 46 -I would suggest 2-3 examples of the immunological analyses that will be performed and of the biomaterial that will be collected in order to provide the reader with a clearer and more specific understanding of the work planned. Following is a suggestion of examples that could be added to the abstract: "In addition, environmental factors are being assessed (e.g. parent's smoking behaviour, dietary factors, antibiotic use, appendicectomy).
In specific centres with the ability to perform extensive immunological analyses (e.g. plasma proteome analysis, peripheral blood T cell analysis, mRNA analysis of biopsies), biomaterial (i.e. blood samples and intestinal biopsies) is being collected and analysed in therapy naïve patients at baseline and during follow-up".
We agree this is an important addition. This was added to the manuscript (page 5, line 80 -85; version with track changes).

4) Introduction is comprehensive, focused and thorough.
Article summary (page 5, lines 14 and 27): Clear and focused.
We thank the reviewer for his compliments.

5) Similarly to my comments above, I would provide a few examples of immunological analysis
and quality of life measures to inform and guide the reader on the specific analyses planned. Example as follows: "Performance of extensive immunological analysis (e.g. peripheral blood cell functional analysis, target quantitative mRNA analysis) of blood and biopsies in therapynaïve patients …" "Large scale-collection of quality of life measures (e.g. IMPACT III and EQ-5D questionnaires) to correlate … " Following this comment we adjusted lines 80 -85 on page 5 of the manuscript (version with track changes).
6) Table 1 on page 9: I would briefly specify how you describe/define disease course, to give the reader a clearer idea of the specific entities analysed. Example as follows: Course of disease (i.e. achievement of remission and/or response to therapy at 3 months, 6 months, 1 year based on wPCDAI, PUCAI; need for treatment escalation within one year; moderate-severe disease during 6-12 months; development of complications such as fibrostricturing disease, penetrating disease, perianal disease; need for surgery; need for biologic use after 1-3-5-10-15 and 20 years).
In Table 1  c. Diet is in the list of environmental factors that will be analysed: how will you be able to correct for variation across different European and Asian populations? Will the assessment be based on questionnaire(s)? If so, which one(s)?
Thank you for this valid remark. When setting up this study we decided that diet questionnaires or diaries would be too time consuming and too complex in this patient group that is already completing several questionnaires. We therefore decided to ask only two questions; 1) whether they are following a vegetarian or vegan diet, and 2) if they are excluding specific items from their diet and if so, for what reason. We clarified this in the revised manuscript in line 277-282 (version with track changes).
8) Eligibility criteria, page 12 line 25 "Children and adolescents < 18 years with a likely or confirmed diagnosis of IBD are eligible." Biomaterial -page 14, lines 20-24 "Patients enrolled in the subcohort in whom the diagnosis of IBD is not confirmed after additional investigations will be analysed as non-IBD controls".
Please provide more information about the number of control patients you are aiming to. Any power calculations for this?

Current data show that approximately 17% of the inclusions in the subcohort are non-IBD controls. As this is a substantial number, we anticipate having sufficient power to detect predominant immune signatures in our patient cohort.
9) Eligibility criteria page 12 line 43 -44: Patients are excluded from this study 1) when they are on similar treatments as for IBD but for other conditions. Please provide some details to this statement. Does this refer to any immune-suppressants and/or corticosteroids and/or biological treatments?

We thank the reviewer for pointing this out. A definition was added to the manuscript (lines 243-247 version with track changes).
10) Recruitment and data collection -Biomaterial -page 14, line 3 "In several centres biological specimens are collected in addition to the clinical data … intestinal biopsies from affected and non-affected tissue are collected prior to treatment initiation …" -Are biopsies going to be collected from specific gut segments? E.g. terminal ileum, right colon, left colon … Will it be the same for Crohn's and UC? Please specify how many biopsies will be collected from which gut location. Figure 1 that depicts the flow chart for collection of biopsies during the endoscopy.

11) Outcome measures page 14
In the absence of a unifying score to categorise disease course in IBD, I fully agree with the choice of primary and secondary outcome measures for this study. Irrespective of whether a patient will be managed with a step-up or top-down approach based on the severity of their disease presentation or course, these outcome parameters are likely to capture the main events reflecting disease severity, that will be subsequently correlated to clinical and environmental variables.
We thank the reviewer for this feedback.

12) Outcome measures -page 15, line 26 -3) the need for surgery
Does this refer to IBD related GI surgery or also to surgery for perianal disease? Please specify.

Both luminal surgery and perianal surgery are recorded in this study. However, for this outcome we will focus on luminal IBD-related surgery as perianal disease is captured under 2) in the list of longer-term secondary outcomes. Changes were made in the manuscript to clarify this (line 328).
13) How many patients have been recruited so far and across how many participating centres? How will you manage missing data/ loss of follow-up?

At this moment 400 PIBD patients have been included in the study in twenty different centers.
We added sentence to the manuscript on the current status of the recruitment.
To reduce the number of missing fields, we have implemented a live system that notifies the sites about missing data and discrepancies. In addition, the data management of the study shares data completion updates with all participating centers on a weekly basis. Due to the large number of participants and to avoid inflation of bias, we are not planning to use any imputation methods. However, we will be focusing on missing at random (MAR) or missing completely at random (MCAR) mechanisms for missing data analysis and thoroughly examine any emerging patterns. Since this is a longitudinal study with repeated measures, we will be using mixed effects models, which are particularly robust to missing visits (lost follow-ups Several papers have been published over the last decade noticing a more severe disease course in paediatric IBD than in adult onset IBD. As the prospective long-term paediatric observational studies are scares, this study is highly relevant and the efforts from the authors in constructing this IBD inception cohort are warmly welcomed. To improve the readability of this paper, however, the authors should revise the language as several sentences are unnecessarily difficult to read due to long sentence structures. Moreover, the main outcome (prediction of complicated disease course and therapy response) should be stated precisely and presented earlier in the protocol.
1) Abstract: a. PIBD is defined as paediatric IBD. As the study period is 20 years, I think this should be changed to paediatric onset IBD. b. Do the authors in truth believe that the inclusion of six countries in Asia and Europe is a Global cohort?
We thank the reviewer for pointing this out and made changes in the manuscript accordingly.
2) Summary: 2nd bullet: I am unsure of how to read this point. Is it a strength/limitation that immunological analyses are performed or is it a strength/limitation that you are testing the performance of the immunological analyses.
The most important strength here is that we obtain extensive immunological data in therapy naïve patients. Subsequently, we are able to follow-up these immunological parameters during the disease course and therapy use. We made changes in the summary section to clarify this.
3) Introduction: a. Same objection to the definition of PIBD as in the abstract. b. The use of the Jess et al reference (number 11) regarding treatment-related adverse effects seems off, as Jess does not report on this subject in the given paper and the main focus is not paediatric onset. Moreover (and importantly), there are several paediatric papers reporting on this specific issue.
We thank the reviewer for pointing this out. The adjustments were made in the introduction, including the insertion of other references. The reference of Jess et al. was removed and references to paediatric studies that describe disease course and the impact of IBD on children's life were added (reference 8, 11-13).

4) Objectives:
a. This section is quite vaguely written, and it seems that the authors here state the aims of the study without any objectives. This is a shame as it would improve the oversight of the study for the reader.
We thank the reviewer for pointing this out. We rewrote this section to clarify our objectives.
b. The authors state that they will assess the impact of diet on disease course, however, I am confused on how the authors will quantify diets. c. It is stated that they will perform a genetic status. To me that means full GWAS, however, this is not planed, as far as I can understand.

As this suggestion is based on
We thank the reviewer for pointing this out. Performing a GWAS in this study was not feasible. Genetic analyses will be performed to determine whether particular patterns of immune responses associate with known genetic risk factors i.e. SNPs. We clarified this in Table 1 so this is in line with the rest of the manuscript.
5) Methods and analysis: a. Table 2: As I understand this is a time-line for the entire study. However, the time-line starts at "time after start of therapy". Should it not be "time from diagnosis"?
Following this comment we adjusted the headings in Table 2.
b. Eligibility: The authors state that a non-validated questionnaire is utilised to assess school attendance. Would it not be worth the while to validate such a questionnaire before deciding to use it in this very ambitious project?
We thank the reviewer for this comment, which is much appreciated. Since it is time consuming to validate such questionnaire and there was (and still is) a clear need for real life data from a paediatric-onset IBD cohort it was decided to, for now, settle with the non-validated questionnaire.
c. Biomaterial: Are the sites of biopsy harvesting standardized or can the biopsies originate from any part of the GI-tract? This will create a very heterogeneous study material difficult to analyse.
The biopsies are collected following a standardized approach. If possible, biopsies from inflamed and non-inflamed tissue are collected from both the ileum and colon. In case the colon is completely affected or unaffected, biopsies should be taken from the transverse colon. Following this comment we adjusted lines 286-294 on page 16 (version with track changes) and added a supplemental figure that depicts the standardized approach for collection of biopsies during the endoscopy in a flow chart.
d. mRNA is not defined.
Thank you for pointing this out. We added a definition.
e. Outcome measures: At baseline, clinical characteristics will be compared in patients with active disease. I am confused. Will all patients not be included at diagnosis and will all patients not have active disease at diagnosis?
We agree this is confusing. We removed ''in children with active disease'' as all PIBD patients will be included to evaluate this.
f. Immunological biomarkers will be evaluated in treatment naïve patients. Are all patients in the study not treatment naïve (with regards to the exclusion criteria)?
We thank the reviewer for pointing this out. All patients in the study are indeed treatment naïve. We adjusted the manuscript to clarify this (lines 304-309, version with track changes).
g. In line 51: location should be localization. h. In line 57: earlier should be early.
Thank you for pointing this out. We corrected the mistakes indicated at point g. and h. in the revised manuscript.
i. Sample size: The authors state that 535 patients are needed. Previously, however, they stated that at least 500 patients would be included. Moreover, on clinicaltrials.gov (clinicaltrials.gov/ct2/show/NCT03571373) they state that 1000 patients will be included. These numbers should be in agreement.

Based on this comment we corrected the incorrect numbers in the manuscript.
According to our formal sample size calculation for the specified primary outcome, which takes into account the UC: CD ratio and drop-outs, we need at least 535 patients. However, this calculation is based on identifying differences in risk factors of 25% or higher and therefore a larger sample size is very welcome. By continuing with recruitment in this observational study up to 1000 patients, we increase our sensitivity and statistical power, also for our secondary outcomes.

Reviewer: 3
Reviewer Name: Denise Herzog Institution and Country: Hôpital cantonal de Fribourg, Switzerland Please state any competing interests or state 'None declared': none With this manuscript the authors publish the protocol of an ongoing global prospective observational study in paediatric IBD (PIBD-SETQuality inception cohort), in order inform interested community members about this study. The most significant new aspect of this protocol is the inclusion of patients before the establishment of the definitive diagnosis. This enables the researchers to examine treatment naive biopsy specimens and blood samples. The second most important aspect is the intended follow-up of twenty years. The collected data will enable the researches to find predictive factors for the different types of disease evolution. The submitted paper is however a summary report of the detailed protocol and therefore some questions remain. However, this calculation is based on identifying differences in risk factors of 25% or higher and therefore a larger sample size is very welcome. By continuing with recruitment in this observational study up to 1000 patients, we increase our sensitivity and statistical power, also for our secondary outcomes. The sample size calculation depends on many key settings (type of variables, variance, sensitivity etc.) and therefore a comparison with the Swiss-IBD cohort study is difficult. The sample size needed to evaluate predictive factors of complicated disease evolution is dependent on the percentage of difference we want to observe. For the primary outcome, this was set at 25%, but for the secondary outcomes a lower difference can be used. Our calculations confirm that we have acceptable power to capture significant effects for the primary endpoint as explained in the protocol. Also, it is very likely that we will exceed the set number of 535 PIBD patients as the current recruitment projections suggest that we will have recruited 550 patients by the end of November 2020. We will aim to extend this observational study in order to obtain sufficient power for all secondary outcomes.

5)
Why do you not take the occasion to collect stool and/or saliva specimens at different time points for microbiological analyses?
We thank the reviewer for this suggestion. We did consider stool collection prior to the start of the study but it was unfortunately not feasible to coordinate and perform this according to high quality standards. Microbiological analysis requires very specific and controlled collection procedures. This would also lead to a significant rise in costs. We could not fulfil these requirements and therefore decided to not perform microbiological analyses.
6) Why do you plan to stop the follow-up after 20 years? A lifelong registry of IBD patients would be of great value.
Thank you for this important comment. Indeed, this would be extremely informative and helpful. Since it already is very challenging to strive for a follow-up of 20 years we will do our ultimate best to achieve this. In case we are successful in doing so and will be able to achieve support for doing so, we might even extend further in future.

REVIEWER
Gasparetto, Marco Cambridge University Hospitals NHS FT, Paediatric Gastroenterology, Hepatology and Nutrition REVIEW RETURNED 21-Mar-2020

GENERAL COMMENTS
As I pointed out on my first revision of this paper, identifying and/or developing prognostic biomarkers in IBD is pivotal to the future care of children and adolescents affected by this condition. There is an urgent need for prognostic biomarkers that will allow an improvement of our quality of care by stratifying patients based on their risk for severe disease and by personalising their treatments accordingly.
For the above reasons, I fully support the realisation and the publication of this work. I had previously suggested a series of amendments that have now been implemented. I am therefore happy for this paper to be published in its current form.